Lesa L. Aylward

Guidelines for the communication of Biomonitoring Equivalents: Report from the Biomonitoring Equivalents Expert Workshop

Biomonitoring Equivalents (BEs) are screening tools for interpreting biomonitoring data. However, the development of BEs brings to the public a relatively novel concept in the field of health risk assessment and presents new challenges for environmental risk communication. This paper provides guidance on methods for conveying information to the general public, the health care community, regulators and other interested parties regarding how chemical-specific BEs are derived, what they mean in terms of health, and the challenges and questions related to interpretation and communication of biomonitoring data. Key communication issues include: (i) developing a definition of the BE that accurately captures the BE concept in lay terms, (ii) how to compare population biomonitoring data to BEs, (iii) interpreting biomonitoring data that exceed BEs for a specific chemical, (iv) how to best describe the confidence in chemical-specific BEs, and (v) key requirements for effective communication with health care professionals. While the risk communication literature specific to biomonitoring is sparse, many of the concepts developed for traditional risk assessments apply, including transparency and discussions of confidence and uncertainty. Communication of BEs will require outreach, education, and development of communication materials specific to several audiences including the lay public and health care providers.

Dioxin risks in perspective: past, present, and future

The United States Environmental Protection Agency (USEPA) and other U.S. and international agencies have focused extensive efforts on the evaluation of the potential health risks of exposures to chlorinated dioxins (PCDDs), furans (PCDFs), and related dioxin-like polychlorinated biphenyls (PCBs). Extensive regulatory efforts over the past 20 years have also been made to control emissions of these compounds and thus to reduce exposures in the general population. This paper reviews the available information on temporal trends in emissions, environmental levels, intake levels through foods, and human body burdens of dioxins. This paper also provides an overview and comparison of recent hazard assessments for dioxins from U.S. and international agencies. Available data on emissions, environmental and food levels, and human body burdens of dioxins in the general population indicate a several-fold reduction in exposures and body burdens in the general population over the three decades from 1970 to 2000. U.S. and international hazard assessments concur on certain aspects, but disagree on fundamental issues including the likelihood of a threshold for carcinogenic dose-response and the degree of safety factors needed in deriving a protective exposure limit. These disagreements have significant consequences for interpreting the potential health risks of current background dioxin exposure levels. However, whatever the degree of health risk that may be associated with current background exposures, the general population is experiencing several-fold lower exposures, and, therefore, lower health risks, currently compared to 30 years ago. In light of the dramatic declines in exposure already observed, further efforts to reduce exposures through attempts to control emissions or food levels should be carefully evaluated to understand the likely efficacy of the efforts and the relative costs and benefits.

Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7–9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDDs carcinogenic potency based on such data.

Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels.

Data on lipid levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the general population in the United States, Canada, Germany, and France over the past 30 years were compiled from the literature. Mean lipid levels of TCDD exhibited a steady decrease by nearly a factor of 10 over this time period, with lipid-adjusted TCDD levels in 2000 about 2 parts per trillion (ppt). Pharmacokinetic modeling using a one-compartment model indicated that absorbed intake levels of TCDD must have decreased by more than 95% from levels in 1972 to result in the observed decrease in human lipid levels, with the bulk of this decrease occurring before 1980. Based on this modeling and the pharmacokinetic properties of TCDD in humans, we conclude that mean levels of TCDD in the general population are likely to decrease further over the next 15 years, to between 0.5 and 1 ppt, even if intake levels do not decrease further. Fewer data over a shorter time period are available for other dioxin and furan congeners in human lipid, but these data indicate substantial decreases as well, with general population TEQ lipid levels currently at least fourfold lower than in 1970 and still decreasing. Food sampling data are limited, but support these trends.

Human biomonitoring assessment values: Approaches and data requirements

Human biomonitoring (HBM) data is a very useful metric for assessing humans exposures to chemicals in commerce. To assess the potential health risks associated with the presence of chemicals in blood, urine or other biological matrix requires HBM assessment values. While HBM assessment values based on human exposure-response data remain the most highly valuable and interpretable assessment values, enough data exists for such values for very few chemicals. As a consequence, efforts have been undertaken to derive HBM assessment values in which external dose based guidance values such as tolerable daily intakes have been translated into equivalent biomonitoring levels. The development of HBM values by the German HBM Commission and Biomonitoring Equivalents by Summit Toxicology has resulted in conceptually similar assessment values. The review of the development of these values provided here demonstrates examples and approaches that can be used to broaden the range of chemicals for which such assessment values can be derived. Efforts to date have resulted in the publication of HBM assessment values for more than 80 chemicals, and now provide tools that can be used for the evaluation of HBM data across chemicals and populations.

Human Response to Dioxin: Aryl Hydrocarbon Receptor (AhR) Molecular Structure, Function, and Dose-Response Data for Enzyme Induction Indicate an Impaired Human AhR

The aryl hydrocarbon receptor (AhR) mediates nearly all studied adverse effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and many related compounds. Binding of TCDD or related ligands to AhR is the key initiating event in downstream biochemical responses. The binding affinity of AhR for TCDD is specific to species and strain, and studies of human AhR demonstrate binding affinities approximately an order of magnitude or more lower than those observed in the most sensitive laboratory strains and species. Molecular genetic studies confirmed that human AhR shares key mutations with the DBA mouse strain that result in an “impaired” AhR (with respect to TCDD binding and responsiveness). Despite a number of polymorphisms in human AhR, the key “DBA-type” mutations appear to be a constant feature of the human AhR, and no polymorphisms have been identified that compensate for the impaired binding function conferred by these mutations. Consistent with the impaired binding status of the human AhR, human cells have consistently required approximately 10-fold higher concentrations of TCDD in vitro than rodent cells to respond with enzyme induction. Recent studies of in vivo enzyme induction-related endpoints in human populations with moderately and highly increased TCDD body burdens detected no relationship between these endpoints and TCDD body burdens at body-burden levels up to 250 ng TEQ/kg body weight, or approximately 25 times above the upper range of current general population background body burdens, while marked elevations in enzyme activity were observed in persons with body burdens above 750 ng TEQ/kg. In contrast, the more sensitive laboratory rodent strains and species exposed to TCDD exhibit significant enzyme induction at body burdens below 50 ng/kg. These interspecies data on the most sensitive and best understood response to binding of TCDD and related compounds to the AhR are consistent with the binding affinity and molecular structure data and support the hypothesis that the human AhR is less functional than the AhR of the more sensitive laboratory animals at a molecular level. Quantitative risk assessments involving interspecies extrapolation from sensitive laboratory species and strains should take these fundamental differences into account when margins of exposure and safety factors are considered. We appreciate the detailed technical assistance and reviews provided by Brent Finley, Robert A. Budinsky, and Shawn Seidel. This article was supported by funding from the Chlorine Chemistry Council.

Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals

Background: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment–based values now allow interpretation of these biomonitoring data in a public health risk context. Objectives: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER. Methods: We identified available risk assessment–based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates. Conclusions: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10–4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.

Advancing Exposure Characterization for Chemical Evaluation and Risk Assessment

A new generation of scientific tools has emerged to rapidly measure signals from cells, tissues, and organisms following exposure to chemicals. High-visibility efforts to apply these tools for efficient toxicity testing raise important research questions in exposure science. As vast quantities of data from high-throughput screening (HTS) in vitro toxicity assays become available, this new toxicity information must be translated to assess potential risks to human health from environmental exposures. Exposure information is required to link information on potential toxicity of environmental contaminants to real-world health outcomes. In the immediate term, tools are required to characterize and classify thousands of environmental chemicals in a rapid and efficient manner to prioritize testing and assess potential for risk to human health. Rapid risk assessment requires prioritization based on both hazard and exposure dimensions of the problem. To address these immediate needs within the context of longer term objectives for chemical evaluation and risk management, a translation framework is presented for incorporating toxicity and exposure information to inform public health decisions at both the individual and population levels. Examples of required exposure science contributions are presented with a focus on early advances in tools for modeling important links across the source-to-outcome paradigm. ExpoCast, a new U.S. Environmental Protection Agency (EPA) program aimed at developing novel approaches and metrics to screen and evaluate chemicals based on the potential for biologically relevant human exposures is introduced. The goal of ExpoCast is to advance characterization of exposure required to translate findings in computational toxicology to information that can be directly used to support exposure and risk assessment for decision making and improved public health.

Sources of Variability in Biomarker Concentrations

Human biomonitoring has become a primary tool for chemical exposure characterization in a wide variety of contexts: population monitoring and characterization at a national level, assessment and description of cohort exposures, and individual exposure assessments in the context of epidemiological research into potential adverse health effects of chemical exposures. The accurate use of biomonitoring as an exposure characterization tool requires understanding of factors, apart from external exposure level, that influence variation in biomarker concentrations. This review provides an overview of factors that might influence inter- and intraindividual variation in biomarker concentrations apart from external exposure magnitude. These factors include characteristics of the specific chemical of interest, characteristics of the likely route(s) and frequency of exposure, and physiological characteristics of the biomonitoring matrix (typically, blood or urine). Intraindividual variation in biomarker concentrations may be markedly affected by the relationship between the elimination half-life and the intervals between exposure events, as well as by variation in characteristics of the biomonitored media such as blood lipid content or urinary flow rate. Variation across individuals may occur due to differences in time of sampling relative to exposure events, physiological differences influencing urinary flow or creatinine excretion rates or blood characteristics, and interindividual differences in metabolic rate or other factors influencing the absorption or excretion rate of a compound. Awareness of these factors can assist researchers in improving the design and interpretation of biomonitoring studies.

Interpreting variability in population biomonitoring data: Role of elimination kinetics

Biomarker concentrations in spot samples of blood and urine are implicitly interpreted as direct surrogates for long-term exposure magnitude in a variety of contexts including (1) epidemiological studies of potential health outcomes associated with general population chemical exposure, and (2) cross-sectional population biomonitoring studies. However, numerous factors in addition to exposure magnitude influence biomarker concentrations in spot samples, including temporal variation in spot samples because of elimination kinetics. The influence of half-life of elimination relative to exposure interval is examined here using simple first-order pharmacokinetic simulations of urinary concentrations in spot samples collected at random times relative to exposure events. Repeated exposures were modeled for each individual in the simulation with exposure amounts drawn from lognormal distributions with varying geometric standard deviations. Relative variation in predicted spot sample concentrations was greater than the variation in underlying dose distributions when the half-life of elimination was shorter than the interval between exposures, with the degree of relative variation increasing as the ratio of half-life to exposure interval decreased. Results of the modeling agreed well with data from a serial urine collection data set from the Centers for Disease Control. Data from previous studies examining intra-class correlation coefficients for a range of chemicals relying upon repeated sampling support the importance of considering the half-life relative to exposure frequency in design and interpretation of studies using spot samples for exposure classification and exposure estimation. The modeling and data sets presented here provide tools that can assist in interpretation of variability in cross-sectional biomonitoring studies and in design of studies utilizing biomonitoring data as markers for exposure.